@article{takeda_ikenaka_fourches_tanaka_nakayama_triki_li_igarashi_tanikawa_ishizuka_2021, title={The VKORC1 ER-luminal loop mutation (Leu76Pro) leads to a significant resistance to warfarin in black rats (Rattus rattus)}, volume={173}, ISSN={["1095-9939"]}, DOI={10.1016/j.pestbp.2021.104774}, abstractNote={Well-known 4-hydroxycoumarin derivatives, such as warfarin, act as inhibitors of the vitamin K epoxide reductase (VKOR) and are used as anticoagulants. Mutations of the VKOR enzyme can lead to resistance to those compounds. This has been a problem in using them as medicine or rodenticide. Most of these mutations lie in the vicinity of potential warfarin-binding sites within the ER-luminal loop structure (Lys30, Phe55) and the transmembrane helix (Tyr138). However, a VKOR mutation found in Tokyo in warfarin-resistant rats does not follow that pattern (Leu76Pro), and its effect on VKOR function and structure remains unclear. We conducted both in vitro kinetic analyses and in silico docking studies to characterize the VKOR mutant. On the one hand, resistant rats (R-rats) showed a 37.5-fold increased IC50 value to warfarin when compared to susceptible rats (S-rats); on the other hand, R-rats showed a 16.5-fold lower basal VKOR activity (Vmax/Km). Docking calculations exhibited that the mutated VKOR of R-rats has a decreased affinity for warfarin. Molecular dynamics simulations further revealed that VKOR-associated warfarin was more exposed to solvents in R-rats and key interactions between Lys30, Phe55, and warfarin were less favored. This study concludes that a single mutation of VKOR at position 76 leads to a significant resistance to warfarin by modifying the types and numbers of intermolecular interactions between the two.}, journal={PESTICIDE BIOCHEMISTRY AND PHYSIOLOGY}, author={Takeda, Kazuki and Ikenaka, Yoshinori and Fourches, Denis and Tanaka, Kazuyuki D. and Nakayama, Shouta M. M. and Triki, Dhoha and Li, Xinhao and Igarashi, Manabu and Tanikawa, Tsutomu and Ishizuka, Mayumi}, year={2021}, month={Mar} }
 @article{triki_kermarrec_visseaux_descamps_flatters_camproux_regad_2020, title={Exploration of the effects of sequence variations between HIV-1 and HIV-2 proteases on their three-dimensional structures}, volume={38}, ISSN={["1538-0254"]}, DOI={10.1080/07391102.2019.1704877}, abstractNote={Abstract HIV protease inhibitors (PIs) approved by the FDA (US Food and Drug Administration) are a major class of antiretroviral. HIV-2 protease (PR2) is naturally resistant to most of them as PIs were designed for HIV-1 protease (PR1). In this study, we explored the impact of amino-acid substitutions between PR1 and PR2 on the structure of protease (PR) by comparing the structural variability of 13 regions using 24 PR1 and PR2 structures complexed with diverse ligands. Our analyses confirmed structural rigidity of the catalytic region and highlighted the important role of three regions in the conservation of the catalytic region conformation. Surprisingly, we showed that the flap region, corresponding to a flexible region, exhibits similar conformations in PR1 and PR2. Furthermore, we identified regions exhibiting different conformations in PR1 and PR2, which could be explained by the intrinsic flexibility of these regions, by crystal packing, or by PR1 and PR2 substitutions. Some substitutions induce structural changes in the R2 and R4 regions that could have an impact on the properties of PI-binding site and could thus modify PI binding mode. Substitutions involved in structural changes in the elbow region could alter the flexibility of the PR2 flap regions relative to PR1, and thus play a role in the transition from the semi-open form to the closed form, and have an impact on ligand binding. These results improve the understanding of the impact of sequence variations between PR1 and PR2 on the natural resistance of HIV-2 to commercially available PIs. Communicated by Ramaswamy H. Sarma}, number={17}, journal={JOURNAL OF BIOMOLECULAR STRUCTURE & DYNAMICS}, author={Triki, Dhoha and Kermarrec, Maxime and Visseaux, Benoit and Descamps, Diane and Flatters, Delphine and Camproux, Anne-Claude and Regad, Leslie}, year={2020}, month={Nov}, pages={5014–5026} }
 @article{cools_triki_geerts_delputte_fourches_cos_2020, title={In vitroandin vivoEvaluation ofin silicoPredicted Pneumococcal UDPG:PP Inhibitors}, volume={11}, ISSN={["1664-302X"]}, DOI={10.3389/fmicb.2020.01596}, abstractNote={Pneumonia, of which Streptococcus pneumoniae is the most common causative agent, is considered one of the three top leading causes of death worldwide. As seen in other bacterial species, antimicrobial resistance is on the rise for this pathogen. Therefore, there is a pressing need for novel antimicrobial strategies to combat these infections. Recently, uridine diphosphate glucose pyrophosphorylase (UDPG:PP) has been put forward as a potential drug target worth investigating. Moreover, earlier research demonstrated that streptococci lacking a functional galU gene (encoding for UDPG:PP) were characterized by significantly reduced in vitro and in vivo virulence. Therefore, in this study we evaluated the anti-virulence activity of potential UDPG:PP inhibitors. They were selected in silico using a tailor-made streptococcal homology model, based on earlier listerial research. While the compounds didn’t affect bacterial growth, nor affected in vitro adhesion to and phagocytosis in macrophages, the amount of polysaccharide capsule was significantly reduced after co-incubation with these inhibitors. Moreover, co-incubation proved to have a positive effect on survival in an in vivo Galleria mellonella larval infection model. Therefore, rather than targeting bacterial survival directly, these compounds proved to have an effect on streptococcal virulence by lowering the amount of polysaccharide and thereby probably boosting recognition of this pathogen by the innate immune system. While the compounds need adaptation to broaden their activity to more streptococcal strains rather than being strain-specific, this study consolidates UDPG:PP as a potential novel drug target.}, journal={FRONTIERS IN MICROBIOLOGY}, author={Cools, Freya and Triki, Dhoha and Geerts, Nele and Delputte, Peter and Fourches, Denis and Cos, Paul}, year={2020}, month={Jul} }